companies who are developing their own therapies.”
In many immunotherapy trials, it’s not just about finding
patients to participate, but also about finding the right patients
– those with the biomarker or targeted mutation most likely to
respond to a given therapy.
According to Ivan Borrello, MD, associate professor of
oncology at Sidney Kimmel Comprehensive Cancer Center at
Johns Hopkins University in Baltimore, Maryland, this is one
of the largest challenges facing immunotherapy. “We have to
answer the questions, ‘Are there subsets of patients who have a
high likelihood of not responding?’ And, conversely, ‘Are there
subsets of patients who are going to be hyper-responsive to these
therapies?’” he said.
Methods to help researchers differentiate patient groups are
“in their infancy,” he noted, and they have yet to be fully incorpo-
rated into trial design and practice, making it difficult to deter-
mine who would be best suited for participation in a given trial.
In myeloma, according to Dr. Borrello, few specific biomark-
ers have been identified to guide treatment decisions in certain
patient groups; however, other forms of cancer are further along
in the use of biomarkers for patient stratification and enrollment.
Using biomarkers as enrollment criteria can sharpen a trial’s
focus, but it also requires more screening and verification upfront,
according to Lisa Butterfield, PhD, professor of medicine,
surgery, and immunology at the University of Pittsburgh Medical
Center’s Hillman Cancer Center. Trials designed to validate a
predicated biomarker must be done in highly regulated, Clinical
Laboratory Improvement Amendments–certified laboratories
by trained professional technologists, which “can add to the
complexity when this becomes part of a trial’s enrollment criteria.”
The success of earlier immunotherapeutic agents presents
another challenge for new agents under investigation, Dr.
Butterfield added: The U.S. Food and Drug Administration
(FDA) has already approved several agents, such as CTLA-4,
PD-1, and PD-L1 inhibitors. The agents are readily available
and used in practice, making it more difficult for researchers to
find an immunotherapy-naïve patient population.
“Everyone goes to the community first,” she explained. “They
are unlikely to come as a newly diagnosed patient to the academic
medical center that’s conducting the new combination trial.”
Weighing the Costs
As more immunotherapy treatments enter the market, the
health-care industry will have to determine whether the clinical
benefits outweigh the high price tags associated with these
treatments.
“Obviously, the more expensive the therapy is, the higher the
therapeutic index is going to have to be,” Dr. Borrello said. “An
expensive therapy is going to have to have a high response rate
and duration of response.”
Treatment with an expensive new agent may not be justified,
for instance, for a patient at the end of life who is unlikely to see
significant improvement.
The editorial board of The Lancet Oncology recognized
this limitation in a recent editorial, calling for a halt in the
“immunotherapy gold rush” to make room for more thorough
investigations of novel drugs. 1 “While heralding an enticing
treatment opportunity, it is essential to bear in mind that the
current generation of immunotherapies merely extends life
expectancy for a small proportion of patients,” the authors
wrote. Before hastily developing their own entry in a new
promising class of drugs, pharmaceutical companies and
researchers should look closely at why a trial failed – or not –
to ensure meaningful benefit for patients, the board wrote.
That many studies are not reproducible “must serve to
temper the degree of off-label use fostering false hope and
the amount of investment in this single line of investigation
when other less-funded research avenues, also with potential
to improve cancer outcomes, remain underexploited,” they
concluded.
Though the costs of conducting trials and moving therapies
through the review pipeline are significant – and manufactur-
ers will likely set their prices to reflect those high investment
costs – Dr. Turtle said that cost-benefit analyses of many of these
therapies may work out in patients’ favor. Potentially curative
chimeric antigen receptor (CAR) T-cell therapies, for instance,
could help patients avoid transplants or years of maintenance
therapy.
“The potential expense of these therapies is heavily crit-
icized, but I think that until their role in overall care is well
defined, it is extremely hard to answer questions about cost
and benefit,” he said.
Exploring Alternate Routes
Immunotherapies are non-traditional, so evaluating their
safety and efficacy through the usual three-phase clinical trial
paradigm seems incongruous. To overcome some of the issues
with recruitment and enrollment, clinical trial designs need to
evolve to suit the types of drugs they are testing, according to
Dr. Butterfield.
Two such strategies include creating more small studies
(rather than a single large trial) that are sufficiently powered
to produce high-quality results, or developing a consortium of
medical centers that allow researchers to draw greater numbers
of patients to one trial.
“We have a consortium of clinical academic medical
centers, each with many myeloma specialty physicians,” she
explained. “That enables us to work across three to six institu-
tions within the same geographic area – eliminating the need
for a larger, nationwide trial and allowing us to run trials in a
shorter amount of time.”
In this era of precision medicine and effective immunother-
apies, “the need for rapid and efficient cancer drug development
has never been greater,” Dr. Butterfield and colleagues argued
in a recent commentary published in the Journal for Immuno-
Therapy of Cancer. 3 “Given the array of avail able targets, drugs,
and biomarkers of response and resistance to therapy, it is clear
that traditional approaches to drug development are unable to
support the speed and level of sophistication required for the
development of effective cancer therapies today.”
The limitations, he noted, are related to the complexities of
answering multiple questions within one clinical trial proto-
October 2017
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